ABSTRACT

There is an increasing interest in microRNAs (miRNAs) as they are of utmost importance in gene regulation at the posttranscriptional level. Sex-related susceptibility for non-communicable diseases later in life could originate in early life. Until now, no data on sex-specific miRNA expression are available for the placenta. Therefore, we investigated the difference by sex of newborn’s miRNA expression in human placental tissue. Within the ENVIRONAGE birth cohort, miRNA and mRNA expression profiling was performed in 60 placentae (50% boys) using Agilent (8 × 60 K) microarrays. The distribution of chromosome locations was studied and pathway analysis of the identified sex-specific miRNAs in the placenta was carried out. Of the total 2558 miRNAs on the array, 597 miRNAs were expressed in over 70% of the samples and were included for further analyses. A total of 142 miRNAs were significantly (FDR<0.05) associated with the newborn’s sex. In newborn girls, 76 miRNAs had higher expression (hsa-miR-361-5p as most significant) and 66 miRNAs had lower expression (hsa-miR-4646-5p as most significant) than in newborn boys. In the same study population, placental differentially expressed genes by sex were also identified using a whole genome approach. The placental gene expression revealed 27 differentially expressed genes by comparing girls to boys. Ultimately, we studied the miRNA-RNA interactome and identified 14 miRNA–mRNA interactions as sex-specific. Sex differences in placental m(i)RNA expression may reveal sex-specific patterns already present during pregnancy, which may influence physiological conditions in early or later life. These molecular processes might play a role in sex-specific disease susceptibility in later life.

摘要

对 microRNA (miRNA) 的兴趣越来越大，因为它们在转录后水平的基因调控中至关重要。晚年与性有关的非传染性疾病易感性可能起源于早年。到目前为止，还没有关于胎盘性别特异性 miRNA 表达的数据。因此，我们研究了人类胎盘组织中新生儿miRNA表达的性别差异。在 ENVIR ON内使用安捷伦 (8 × 60 K) 微阵列对 60 个胎盘（50% 男孩）进行 AGE 出生队列、miRNA 和 mRNA 表达谱分析。研究了染色体位置的分布，并对胎盘中鉴定的性别特异性miRNA进行了通路分析。在阵列上总共 2558 个 miRNA 中，597 个 miRNA 在超过 70% 的样本中表达，并被包括在内以进行进一步分析。共有142个miRNA与新生儿性别显着相关（FDR<0.05）。在新生女孩中，76 个 miRNA 的表达高于新生男孩（hsa-miR-361-5p 最显着），66 个 miRNA 表达较低（hsa-miR-4646-5p 最显着）。在同一研究人群中，还使用全基因组方法鉴定了按性别划分的胎盘差异表达基因。通过比较女孩和男孩，胎盘基因表达揭示了 27 个差异表达的基因。最终，我们研究了 miRNA-RNA 相互作用组，发现 14 种 miRNA-mRNA 相互作用具有性别特异性。胎盘 m(i)RNA 表达的性别差异可能揭示怀孕期间已经存在的性别特异性模式，这可能会影响早年或晚年的生理状况。这些分子过程可能在晚年的性别特异性疾病易感性中发挥作用。